Obesity has increased at a fast rate in recent years and is now a worldwide public health problem. The major consequence of overweight and obesity is that they are associated with more than 30 medical conditions, which cause approximately 300,000 deaths and total medical expenditures (direct and indirect) of $139 billion annually in the USA alone (Finkelstein E A, Ruhm C J, Kosa K M (2005) Economic Causes and Consequences of Obesity. Annu Rev Public Health 26: 14.1-14.19). Insulin resistance, a characteristic of obesity, prevents insulin from taking the sugar from food and distributing it throughout the body for energy. Many studies have clearly indicated that intramyocellular accumulation of triglycerides is a major contributor to insulin resistance (Goodpaster B H, Wolf D (2004) Skeletal muscle lipid accumulation in obesity, insulin resistance, and type 2 diabetes. Pediatr Diabetes 5: 219-226).
Therefore, identification of genes associated with intramyocellular lipid accumulation would provide a clear target for pharmaceutical intervention and care for obesity and its related conditions, such as high blood pressure, type 2 diabetes, coronary heart disease, some types of cancer, poor female reproductive health and psychological disorders.
Urocortin 3 (UCN3) is a member of the corticotropin-releasing hormone (CRH) family of peptides. UCN3 binds selectively to CRHR2 (Lewis K, Li C, Perrin M H, Blount A, Kunitake K et al. (2001) Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc Natl Acad Sci USA 98: 7570-7575) and both are co-expressed throughout the central nervous system, such as in the ventromedial hypothalamic nucleus, lateral septum and bed nucleus of the stria terminalis (Li C, Vaughan J, Sawchenko P E, Vale W W (2002) Urocortin III-immunoreactive projections in rat brain: partial overlap with sites of type 2 corticotrophin-releasing factor receptor expression. J Neurosci 22: 991-1001), as well as in the gastrointestinal tract (Zorrilla E P, Tache Y, Koob G F (2003) Nibbling at CRF receptor control of feeding and gastrocolonic motility. Trends Pharmacol Sci 24: 421-427). UCN3 is, therefore, thought to play a central role in appetite and gastrointestinal motor regulation. For example, intracerebroventricular injections of UCN3 were found to reduce appetite by suppressing food intake in the freely-fed rat (Ohata H, Shibasaki T (2004) Effects of urocortin 2 and 3 on motor activity and food intake in rats. Peptides 25: 1703-1709).
On the other hand, there is increasing evidence supporting the involvement of this peptide in the regulation of energy homeostasis and in mediating the anorexic effect of CRH at the adipose level. For example, Seres and colleagues (Seres J, Bornstein S R, Seres P, Willenberg H S, Schulte K M et al. (2004) Corticotropin-releasing hormone system in human adipose tissue. J Clin Endocrinol Metab 89: 965-970) found that UCN3 is expressed in human visceral and subcutaneous adipose tissue. Obviously, the local production of this peptide within the adipose tissue indicates its direct involvements in fat cell function in addition to its central effects on weight regulation. Thus, Applicants hypothesized that genetic polymorphisms of UCN3 are associated with muscle fat deposition and subcutaneous fat depth (SFD) in mammals.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.